Abstract：
Metabolic reprogramming is a hallmark of cancer. The nicotinamide phosphoribosyltransferase (NAMPT)-mediated salvage pathway maintains sufficient cellular NAD levels and is required for tumorigenesis and development. However, the molecular mechanism by which NAMPT contributes to HBV-associated hepatocellular carcinoma (HCC) remains not fully understood. In the present study, our results showed that NAMPT protein was obviously upregulated in HBV-positive HCC tissues compared with HBV-negative HCC tissues. NAMPT was positively associated with aggressive HCC phenotypes and poor prognosis in HBV-positive HCC patients. NAMPT overexpression strengthened the proliferative, migratory, and invasive capacities of HBV-associated HCC cells, while NAMPT-insufficient HCC cells exhibited decreased growth and mobility. Mechanistically, we demonstrated that NAMPT activated SREBP1 (sterol regulatory element-binding protein 1) by increasing the expression and nuclear translocation of SREBP1, leading to the transcription of SREBP1 downstream lipogenesis-related genes and the production of intracellular lipids and cholesterol. Altogether, our data uncovered an important molecular mechanism by which NAMPT promoted HBV-induced HCC progression through the activation of SREBP1-triggered lipid metabolism reprogramming and suggested NAMPT as a promising prognostic biomarker and therapeutic target for HBV-associated HCC patients.
摘要：
代谢重编程是癌症的标志。烟酰胺磷酸核糖基转移酶（NAMPT）介导的补救途径保持足够的细胞NAD水平，是肿瘤发生和发展所必需的。然而,NAMPT促成HBV相关肝细胞癌(HCC)的分子机制尚不完全清楚.在本研究中,我们的结果表明，与HBV阴性HCC组织相比，HBV阳性HCC组织中NAMPT蛋白明显上调。NAMPT与HBV阳性HCC患者的侵袭性HCC表型和不良预后呈正相关。NAMPT过表达增强了增殖，迁徙,和HBV相关肝癌细胞的侵袭能力，而NAMPT不足的HCC细胞表现出降低的生长和移动性。机械上,我们证明NAMPT通过增加SREBP1的表达和核易位来激活SREBP1(固醇调节元件结合蛋白1),从而导致SREBP1下游脂肪生成相关基因的转录以及细胞内脂质和胆固醇的产生.总之,我们的数据揭示了NAMPT通过激活SREBP1触发的脂质代谢重编程促进HBV诱导的HCC进展的重要分子机制,并表明NAMPT是HBV相关HCC患者的有希望的预后生物标志物和治疗靶点.
